Pneumonic plague is the deadliest form of disease caused by Yersinia pestis. The rapid progression of pneumonic plague, along with the ability to transmit it by an aersolized form make it a deadly bioterrorism threat. In this project, we will characterize the interaction between Yersinia pestis and airway epithelial cells using an in vitro model of infection. Primary cultures of rat pneumocytes will be infected with bacterIa, and we will characterize both the bacterial and host responses to infection using a variety of techniques, including microarray analyses. We will extend these studies to the hamster tracheal organ culture system developed by our laboratory and use these to study Y. pestis wild type organisms, as well as mutants of Yersinia lacking one or more of the three virulence plasmids. These studies will tell us more about how Yersinia interacts with host respiratory cells, and may provide new targets for therapeutics and plague vaccines.